ANALYSIS:

CORONAVIRUS

How a (corona) virus resides in your cells like a hand blender

What kind of creature is the coronavirus? The virologists who were
already studying it before the world news became impressed in any case.
"Look, now he's building a nest."





Maarten Keulemans March 6, 2020, 12:14 PM

There. Those small, round grains on the microscope photo: they are. The virus particles that
are the talk of the day, from Asia to America, and from Loon op Zand to Lombardy. The virus
for which the world holds its breath. The corona virus.
In a small office at the back of the LUMC, university lecturer Montse Bárcena turns the
wheel of her computer mouse. The virus particles approach on a flat screen on the wall.
Round, gray spots that dance around the animal cells that Bárcena infected with virus and
photographed with the electron microscope. Not the real Wuhan virus, by the way - which
was not yet available when she was doing her experiments - but the Sars virus, that closely
related, other Asian corona virus that ravaged the world eighteen years ago.
They are small. Incredibly small. Quite a few people think that a virus is about the same as a
bacterium (both small and itchy), but in reality, in terms of size and complexity, a virus
compares to a bacterium like a rowboat to an aircraft carrier. In essence, a bacteria is still a
small animal, but a virus is no more than a wrapped string of hereditary material, with the
inscription: COPY ME.

Image Thomas Nondh Jansen


The virus sends that message to your body, hoping your cells will do the job. Fascinating,
Bárcena thinks. That such a tiny crumb has so much to offer. "They are actually very small,
extremely complicated molecular machines," she points to the spheres. "So sophisticated."
Viruses are therefore the invisible hand behind all kinds of biological processes. That you
can process starch, and that the body of female mammals tolerates a baby: it has to do with
subtle genetic signals in the DNA that viruses have introduced there. There are even
scientists who think that the virus was there before life itself: viruses form the canvas on
which the story of life is painted.
But don't confuse them with living things, emphasizes professor of virology Eric Snijder
(LUMC). Because they may be made of the same molecular stuff as you and me, without a
host they can't multiply. According to most definitions, that really makes viruses as lifeless
as a package of mail. "Multiply. Pack yourself. And go to the next host, "is how Snijder
describes the mission of the viruses. A virus does not think, does not feel, does not hesitate.
It just does.
It all starts when some virus enters our body. By inhalation, perhaps through the eyes: if you
are a ten thousandth of a millimeter small, there is always a way in. Once there, the virions,
as the virus particles are formally called, tumble and float through your airway. Until they
bite.
To do this, the coronavirus uses one of the petal-like protrusions that surround it and give it
the name "coronavirus" (after the "crown" of the protrusions). His "spikes". The virus scans
its environment with it. Until the spikes are chemically attached to a cap on the outside of
human airway cells called ACE2. Contact.
After which the virus can be packaged willingly in a vesicle in which the cell also packs useful
nutrients and bubbles in, hop into the cell. There the cell begins, unsuspectingly, to unpack
the package. With numerous busy hands, proteins strip the fat vesicle from him and break
open his outside. Until its unholy content is released. His hereditary material. COPY ME.
That genetic recipe book, the 'genome', distinguishes coronaviruses from many other
viruses, says Snijder. The polio virus contains a genome of 7,500 chemical letters; the new
coronavirus has 29,903 letters of genetic instructions. About as many letters as in this
science section.
Not that the virus is suddenly more powerful or dangerous than polio: it doesn't work that
way. "It is more that he has more tricks on board. His multiplication in the cell is more
refined, smoother," says Snijder.

Model of the virus that causes Covid-19. Image EPA


In the cells of your airways, the coronavirus begins to unroll its massive genome. Written in
chemical code language, a long string of hereditary material that biologists call "RNA".
Slavely, the protein factories in your cells begin to follow the building instructions on the
RNA. Sixteen parts are tinkering them out.
A tool of the devil, as it will soon become clear. The virus components start to click together.
Until a huge, complex protein complex called "replicase" is created. "Those sixteen products
are parts of a copier," says Snijder. "And a copier is what you get when they find each
other."
Genetically, the new coronav virus is simply a sars virus, says coronavirologist Raoul de
Groot (Utrecht University). We see a huge gene: the instructions for the copier, COPY ME.
Behind that is a somewhat smaller gene, which indicates how the spike protein should be
made: HOW TO MAKE MY PROJECTS.
And behind that, a genetic postscript almost, a triad of seven shorter genes. Two with the
recipe for the virus particle shell. One with the instruction for the packaging of the genome.
And sandwiched in between six genes that the virus probably uses to get things going
better. "Sars the second is just a variation on the same theme," says De Groot. "A copier
with a toolbox behind it that is basically the same as what we know from sars the first."
No wonder virologists have also officially started calling the virus "SARS-CoV-2",
sarscoronavirus number two. Put the hereditary material of the new coronavirus next to
that of the sars virus, and 80 percent agree with the 'text' - in many places the viruses are
almost identical.
One of the most fascinating differences, as far as De Groot is concerned, is in a small gene
called "ORF 8", one of the auxiliary genes in the toolbox. Nobody knows exactly what the
gene does: in Sars the first it was broken, because 29 letters had been dropped from it. So it
probably won't be that important, most researchers assumed.
Until two years ago, German virologist Christian Drosten investigated what happens when
you repair the gene. To his surprise he saw that the virus got a huge boost: number 8
appears to increase the copying speed of the virus more than twenty times.
"And now it is coming," says De Groot. "In Sars 2, this gene is still intact." Could that be why
the new coronavirus spreads so smoothly? It is "pure speculation", emphasizes De Groot.
But of course it makes sense. "Cells have all kinds of defense systems to stop viruses. I
suspect it may well be that ORF 8 plays a role in avoiding those mechanisms. "
In your cells, the virus has started the next phase. A wonderful phase, as can be seen in the
microscope photos of Bárcena: the virus starts blowing bubbles. A kind of foam is created in
the cell, from double-walled bubbles. "At first we thought it was an accidental side effect,"
said Bárcena, who studies the bubbles. "We now assume that it is an essential part of the
replication cycle."
After all, the bubbles are not isolated, according to the Leiden research. Rather, they are
cocoons, interconnected by a kind of web of wires. The virus is making them through its
proteins to convert the "endoplasmic reticulum", a series of membranes in the cell that
enjoys some fame as a difficult part of the biology class to remember. "Look," says Snijder,
pointing to the microscope photos of Bárcena. "The virus is building a nest."
Snijder and Bárcena suspect the virus might need that litter to have solid ground underfoot
when copying its hereditary material. In any case, new strands of virus RNA are starting to
form in and on the cocoons. Further on, in the still intact endoplasmic reticulum, the spike
proteins are now starting to grow, like mushrooms in a nursery.
It's starting to get out of hand, in there. The newly made RNA is packaged, drifts, pulls
through the spike-overgrown membranes, and gets trapped under the spikes, like you get
under the twigs as you squeeze through thickets. Slowly new virus particles start to form.
Not one or two, but thousands per cell. It takes about ten or twelve hours before the first
viruses leave the cell in each vesicle. On the way to the next cell, another ACE2 cap to suck
on. COPY ME! COPY ME! COPY ME! - from endless molecular throats at the same time.
And this is what you have left, gestures Montse Bárcena. With the wheel of her computer
mouse she zoomed out a bit to survey the battlefield. We see the infected cell, or what is
left of it. An exhausted chaos, in which little of the individual cell structures can be
recognized. Like a hand blender, the virus has raged in the delicate interior of the cell. The
endoplasmic reticulum has turned into a lumpy knit. And everywhere there are loose spikes,
idly RNA strings and discarded proteins that the virus has left behind.
That is not all, because spikes also stick to the outside of the cell. As a result, cells start to
stick together, nutrient molecules and signal substances can no longer pass and entire
tissues become diseased. Until the cell self-inflates, it is broken down by immune cells or a
bacterium comes by to feast on the diseased cell porridge. You cough: the bacteria, the
waste and the core healthy virus particles fly around.
Who could have imagined that the coronavirus would turn the world around like that, says
Raoul de Groot, who once obtained his doctorate on a cat coronavirus and now specializes
in a cold virus that spread to humans from cows. "If you wanted name and fame, you
started working on HIV or hepatitis C, viruses that cause serious human diseases. Not a virus
that only makes your cat sick, like me. "
But blame the virus for something. That does not think, does not feel, just acts.
"This is now the third time this has happened," said Snijder, referring to the sars crisis and
deadly "dromedary disease" in the Middle East. "Every now and then we are punished for
our carelessness in disturbing the balance in nature. The virus takes its chance. That does
not work every day. But if you give him a million times the chance, it should work. "
Postscript: This piece is written as a virus is composed, from loose elements that were put
together afterwards. Like a virus, I took a few short passages from other work: the two
opening sentences are from an earlier article, the passage of the rowing boat and the
aircraft carrier from a book I wrote ten years ago. The mid-point typo (coronavv virus) is in
the exact position, at 44 percent of the text, where the coronavirus also has a hitch called a
"frameshift." When reading this piece, you probably got distracted here, just like a real cell
does when it reads the viral RNA.

Infected animal cells with the coronavirus, the granules.Image Montserrat Bárcena, LUMC

Coronavirus particles, zoomed in. Image Montserrat Bárcena, LUMC



Counting viruses

It is difficult to say exactly how many viruses there are. The boundary between species is
often difficult to draw, because viruses, like the colors blue and green, overlap. According to
an American estimate, about half a million viruses circulate in mammals alone. Estimates
about the total number of virus types therefore quickly amount to tens or hundreds of
millions. About fifty of the coronaviruses are known.

Coronavirus

In preparation for a possible crisis situation such as in China or Italy, the association of
intensive care physicians sent a "scenario pandemic" to members on Monday. "In the most
extreme case, we can no longer take in people over the age of 80."
What started as a mysterious virus in the Chinese metropolis of Wuhan has spread all over
the world. The Netherlands has now also been infected with the corona virus. In this file you
can read everything we write about the virus.
Many empty classes in Brabant: "Children greet each other with their feet or elbows."
Dirk Jan, himself a doctor, contracted corona: "A nice exercise for a more dangerous virus".
After European stock markets, Wall Street is also falling sharply.